ABSTRACT Non-human primate (NHP) models have been recommended as ideal animal models for preclinical, translational stroke research by the Stroke Therapy Academic Industry Roundtable (STAIR) committee due to translational failures in rodents and significant cerebrovascular, neuroanatomical and biomolecular similarities between NHPs and humans. In response to this recommendation, Dr. Nudo (one of PIs on the current proposal), has pioneered and further developed NHP stroke models in the past few decades. Although clinically-relevant NHP stroke models are now available, limitations in imaging modalities that can map neural activates in deep brains of awake monkeys are hindering the current research. Functional magnetic resonance imaging (fMRI) has been widely used to detect functional changes in the brain. However, this technique is limited by poor temporal and spatial resolution when collecting functional information. Particularly, for brain research involving awake, behaviorally active monkeys, the limited temporal resolution of fMRI can be a significant barrier because of motion artifacts. Alternatively, many studies have used chronic, invasive microelectrode implants for recording action potential and local field potentials in awake monkeys; however, microelectrode electrical recording is quite invasive, has poor spatial resolution, and does not provide depth-resolved information. We propose to develop a wearable, whole brain imaging system based on the emerging photoacoustic (PA) imaging (PAI) for ischemic stroke research with NHP models. Ischemic stroke is characterized by changes in hemodynamics in the brain. Triggered by the occlusion of a major cerebral artery or its branches, ischemic stroke leads to cerebrovascular adaptations both acutely and chronically. PAI, based on optical absorption contrast, is intrinsically sensitive to the changes in brain hemodynamics including both blood volume (perfusion) and blood oxygenation (oxygen consumption). Therefore, PAI offers excellent ability to understand the acute and chronic cerebrovascular adaption after stroke, as well as hemodynamic changes resulting from functional activation in the brain. Built on our strong expertise in PA brain imaging, especially in PAI of an awake behaviorally active rhesus monkey, we propose to develop a real-time wearable PA brain imaging system that can be used for deep brain mapping through a cranial window. By utilizing state-of-the-art capacitive micromachined ultrasonic transducer (CMUT) technology, the proposed PAI technology can provide depth-resolved functional information in deep brain regions in real-time with high spatial resolution. Two aims are proposed: 1) Evaluate and optimize a wearable, multi-wavelength CMUT-based PAI system for real-time visualization of functional activation in the NHP brain; and 2) Image changes in brain functional activations and cerebrovascular adaptations in an NHP stroke model in a longitudinal study. The success of this study will provide answers to important scientific questions about stroke with NHP models, and pave the way for new stroke therapy development.